A Critical Interaction between NR2B and MAGUK in l-DOPA Induced Dyskinesia

Abstract

Abnormal function of NMDA receptor has been suggested to be correlated with the pathogenesis of Parkinson's disease (PD) as well as with the development of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. Here we show that NMDA receptor NR2 subunits display specific alterations of their subcellular distribution in striata from unilateral 6-hydroxydopamine-lesioned, L-DOPA-treated dyskinetic, and L-DOPA-treated nondyskinetic rats. Dyskinetic animals have significantly higher levels of NR2A subunit in the postsynaptic compartment than all other experimental groups, whereas NR2B subunit shows a significant reduction in both dopaminedenervated and dyskinetic rats. These events are paralleled by profound modifications of NMDA receptor NR2B subunit association with interacting elements, i.e., members of the membrane-associated guanylate kinase (MAGUK) protein family postsynaptic density-95, synapse-associated protein-97 and synapse-associated protein-102. Treatment of nondyskinetic animals with a synthetic peptide (TAT2B) able to affect NR2B binding to MAGUK proteins as well as synaptic localization of this subunit in nondyskinetic rats was sufficient to induce a shift of treated rats toward a dyskinetic motor behavior. These data indicate abnormal NR2B redistribution between synaptic and extrasynaptic membranes as an important molecular disturbance of the glutamatergic synapse involved in L-DOPA-induced dyskinesia.

Acid-sensing ion channel 1a is required for mGlu receptor dependent long-term depression in the hippocampus

“…As previously reported [25], TIF has been used instead of the classical post-synaptic density (PSD) because the amount of the starting material was very limited.…”

“…Using a well-established post-synaptic-enriched biochemical preparation [25], we isolated the triton insoluble fraction from pharmacological treated brain slices. In line with previous results [34], we found that the levels of p-GluA1/GluA1 ratio were significantly increased upon DHPG treatment compared to control (control n = 4 vs. DHPG n = 4; p < 0.01) (Fig.…”

Effect of rasagiline on the molecular composition of the excitatory postsynaptic density

“…Interestingly, MAO-B inhibitors have been shown to partially protect neurons against overactivation of NMDA receptors without interfering with their physiological function (Niittykoski et al, 2003). This is intriguing since NMDA receptor is altered in experimental parkinsonism (Dunah and Standaert, 2001;Paillé et al, 2010), during development of L-DOPA induced dyskinesia (Gardoni et al, 2006) and in patients (Calon et al, 2003). In addition, synaptic localization of NMDA receptor subunits, namely NR2A and NR2B, and their functional interactions with scaffolding elements of the PSD-MAGUK protein family have been shown to be crucial to the pathogenesis of Parkinson's disease and to the development of L-DOPA induced dyskinesia (Gardoni et al, 2006;Picconi et al, 2004).…”

“…This is intriguing since NMDA receptor is altered in experimental parkinsonism (Dunah and Standaert, 2001;Paillé et al, 2010), during development of L-DOPA induced dyskinesia (Gardoni et al, 2006) and in patients (Calon et al, 2003). In addition, synaptic localization of NMDA receptor subunits, namely NR2A and NR2B, and their functional interactions with scaffolding elements of the PSD-MAGUK protein family have been shown to be crucial to the pathogenesis of Parkinson's disease and to the development of L-DOPA induced dyskinesia (Gardoni et al, 2006;Picconi et al, 2004). In a rat model of early Parkinson's disease, normalization of the aberrant synaptic localization of NR2A subunits rescued the motor symptoms (Paillé et al, 2010).…”

Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-d-aspartate neurotoxicity

“…Because of the discrete pre-and postsynaptic, and intraand extrasynaptic, localization of the various receptor subunits (Bernard and Bolam, 1998;Wang and Pickel, 2000;Dunah and Standaert, 2003;Galvan et al, 2006), striatal NMDA receptor stimulation has multiple and complex functional effects. Moderate activation of NMDA receptors controls, for example, monoaminergic, cholinergic, glutamatergic and peptidergic neurotransmission (Becquet et al, 1990;Young and Bradford, 1993;Knauber et al, 1999;Hathway et al, 2001;Radke et al, 2001;Marti et al, 2005) and, as a consequence, affects synaptic plasticity (Centonze et al, 2004;Dang et al, 2006), motor function (Hallett et al, 2005;Gardoni et al, 2006) and cellular bioenergetics (Moncada and Bolanos, 2006 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.…”